CD4+ T cells play a fundamental role in orchestrating immune responses. Aberrant T lymphocyte signaling underlies the pathogenesis of numerous diseases including autoimmunity, asthma and allergy. Therefore, unraveling the signaling pathways that govern T helper lineage commitment and function is crucial toward gaining a better understanding the molecular basis underpinning these disease states. An increase in intracellular calcium ion concentration ([Ca2+]i) is an essential signal that regulates numerous T cellular functions. Variations in both the amplitude and duration of Ca2+ signaling patterns differentially regulate transcriptional programs in lymphocytes, yet little is understood as to which Ca2+ channels mediate these signals and consequently control T cell differentiation. The T-type channel CaV3.1, best known for its role in brain and cardiac function, is expressed on nave T lymphocytes, regulates a Ca2+ entry at resting membrane potentials and is dramatically up-regulated during Th2 differentiation. Genetically deleting CaV3.1 in T lymphocytes decreases baseline Ca2+ influx, has no impact on store-operated Ca2+ entry (SOCE) and skews the cells towards Th1 differentiation. Moreover, deleting CaV3.1 prevents Gata-3 expression while favoring T-bet expression. These observations provide evidence that CaV3.1 T-type Ca2+ channels regulates Th1/Th2 polarization and suggest a surprising role for CaV3.1- mediated Ca2+ entry in T lymphocyte differentiation. The objective of this application is to fully characterize the function of CaV3.1 as it relates to Th lymphocyte differentiation and function. We propose experiments to define the requirement of CaV3.1 in Th differentiation (Aim 1), dissect the signaling pathways that CaV3.1 regulates (Aim 2) and determine if it regulates Th2 responses that underlie common immune diseases such as asthma and various allergies (Aim 3). We anticipate that the outcomes of the proposed experiments will greatly enhance our understanding of the molecular nature of Ca2+ signaling events required to shape T cell differentiation. PUBLIC HEALTH RELEVANCE: Defects in T cells, which are important part of the immune system required to fight disease and infection, underlie several diseases such as autoimmunity, asthma and allergy. We have identified a molecule that may regulate T cells in these disorders. Studying the function of this molecule in T cells may lead to better therapies to treat these disorders.